An ion mobility spectrometer is typically composed of an ionization source, a drift cell, and an ion detector; examples of the latter include a sampling plate, an electron multiplier, or a mass spectrometer. Ion mobility spectrometry separates ions in terms of their mobility with reference to a drift/buffer gas measuring the equilibrium velocity which ions obtain. When gaseous ions in the presence of a drift gas experience a constant electric field, they accelerate until a collision occurs with a neutral molecule. This acceleration and collision sequence is repeated continuously. Over time, this scenario averages out over the macroscopic dimensions of the drift tube to a constant ion velocity based upon ion size, charge and drift gas pressure. The ratio of the velocity of a given ion to the magnitude of the electric field experienced by it is the ion mobility. In other words, the ion drift velocity (vd) is proportional to the electric field strength (E) where the ion mobility K=vd/E is a function of the ion volume/charge ratio. Thus IMS is a technique similar to mass spectrometry, having a separation component to it. IMS is generally characterized as having high sensitivity with moderate separation power. Separation efficiency is compromised when “bands” of the various ions spread apart as opposed to remaining together in a tight, well-defined plug. Thus, the quality of the electric field maintained in the drift cell is critical to preserving and perhaps improving separation efficiency; i.e., resolution. It is also critical in applications where a downstream detection method is limited by ion throughput from the ion mobility drift cell. Improved focusing improves ion throughput to the downstream instrumental detection platform, thereby improving overall performance.
Prior art instruments employ various methods to obtain a linear electric field including utilizing: 1) a series of equally spaced rings connected through a resistor chain, 2) a tube coated with a resistive material in U.S. Pat. No. 4,390,784 to Browning et al., or 3) by a more complex method such as a printed circuit board assembly drift tube in U.S. Pat. No. 6,051,832 and PCT WO 98/08087 to Bradshaw. Von Helden (G. Von Helden, T Wyttenbach, M. T. Bowers Science 267 (1995) p 1483) showed transport of MALDI ions desorbed from a surface and transported into a 1 Torr mobility cell and In 1995 Bristow showed the use of a MALDI matrix surface to generate ions inside an atmospheric ion mobility spectrometer (A. W. T. Bristow, C. S. Creaser, J. W. Stygall “Matrix Assisted Laser Desorption Ionisation-Ion Mobility Spectrometry, Abstract to Fourth International Workshop on Ion Mobility Spectrometry,” Cambridge U.K. Aug. 6–9, 1995).
The combination of an ion mobility spectrometer (IMS) with a mass spectrometer (MS) is well known in the art. In 1961, Barnes et al. were among the first to combine these two separation methods. Such instruments allow for separation and analysis of ions according to both their mobility and their mass, which is often referred to as two dimensional separation or two dimensional analysis. Young et al. realized that a time-of-flight mass spectrometer (TOFMS) is the most preferred mass spectrometer type to be used in such a combination because its ability to detect simultaneously and very rapidly (e.g. with a high scan rate) all masses emerging from the mobility spectrometer. Their combination of a mobility spectrometer with a TOFMS, in the following referred to as a Mobility-TOFMS. This prior art instrument comprised means for ion generation, a mobility drift cell, a TOFMS, and a small orifice for ion transmission from the mobility cell to the TOFMS.
Use of MS as a detector allows for resolution based on mass-to-charge ratio after separation based upon ion mobility. Shoff and Harden pioneered the use of Mobility-MS in a mode similar to tandem mass spectrometry (MS/MS). In this mode, the mobility spectrometer is used to isolate a parent ion and the mass spectrometer is used for the analysis of fragment ions (also called daughter ions) which are produced by fragmentation of the parent ions. In the following this specific technique of operating a Mobility-MS is referred to as Mobility/MS, or as Mobility/TOF if the mass spectrometer is a TOFMS-type instrument. Other prior art instruments and methods using sequential IMS/MS analysis have been described (see, e.g., McKnight, et al. Phys. Rev., 1967, 164, 62; Young, et al., J. Chem. Phys., 1970, 53, 4295; U.S. Pat. Nos. 5,905,258 and 6,323,482 of Clemmer et al.; PCT WO 00/08456 of Guevremont) but none combine the instrumental improvements disclosed presently. When coupled with the soft ionization techniques and the sensitivity improvements realizable through use of the drift cell systems herein disclosed, the IMS/MS systems and the corresponding analytical methods of the present invention offer analytical advantages over the prior art, particularly for the analysis of macromolecular species, such as biomolecules.
The challenging issue when building a Mobility-MS is achieving a high ion transmission from the mobility region into the MS region of the tandem instrument. It is at this interface that the earlier goals of ion mobility technology of using a linear field appear incongruous with the goal of maximizing ion throughput across the IMS/MS interface. The mobility section is operating at a pressure of typically between 1 mTorr and 1000 Torr whereas the MS is typically operating at pressures bellow 10−4 Torr. In order to maintain this differential pressure it is necessary to restrict the cross section of the opening that permits the ions to transfer from the mobility section to the MS section. Typically this opening cross section is well below 1 mm2. Hence it is desirable to focus the ions into a narrow spatial distribution before this transmission occurs.
As discussed above, in the early development of IMS, it was believed that the use of focusing methods (i.e., non-linear fields) was detrimental because it was believed that such focusing methods would deteriorate the resolution of the mobility spectrometer. Also, many of the early mobility spectrometers were used to investigate the mobility constant of ions, in which case it is preferable to use a homogeneous field of known value along the ion drift path. Therefore, most instruments simply used a large area ion detector at the end of the mobility drift and ion focusing was not an overarching concern. It was only when the need for compact and sensitive IMS emerged when the focusing of the drift ions was addressed.
In U.S. Pat. No. 4,855,595, Blanchard taught a focusing method based on time-varying electric fields. In 1992, Avida et al. U.S. Pat. No. 5,235,182 found that a slight inhomogeneous fringe fields along the mobility drift cell could be used to reduce the loss of ions from the edge of the mobility drift cell and hence to reduce the size of mobility instruments. The inhomogeneous fringe fields were generated by simply increasing the thickness of the field-generating ring electrodes such that the ratio of electrode thickness to inter-electrode gap could be manipulated to provide the fringe fields. The following year, Thekkadath (U.S. Pat. No. 5,189,301) taught a cup shaped electrode to generate a focusing field. This field configuration compares to the Vehnelt cylinder used in non-collisional ion optics. In 1996 Gillig et al. published a magnetic field to confine the ions in a small beam in order to increase the ion transmission from the mobility section into a mass spectrometer.
In 1999 Gillig used a periodic configuration of focusing and defocusing fields in order to increase the ion transmission from the mobility section into the MS section, as discussed above. This field configuration compares to a technique used in non-collisional ion optics where series of focusing and defocusing lenses are used to confine ion beams in large ion accelerators [Septier, p. 360]. Published U.S. application nos. 2001/0032930 to Gillig et al. and 2001/0032929 to Fuhrer et al. taught the use of a specific mobility cell electrode configuration to produce periodic and periodic/hyperbolic fields, respectively and superior focusing. U.S. Pat. No. 6,040,575 to Whitehouse et al., teaches surface charging of insulators to collect and slow down or selectively fragment the ions in the region of the orthogonal time-of-flight mass section.
Nonlinear electric fields have also been introduced to ion mobility drift cells to focus ions to a detector as presented in U.S. Pat. No. 5,189,301 to Thekkadath utilizing a cup electrode and U.S. Pat. No. 4,855,595 to Blanchard using nonlinear fields for the purpose of controlling ions, trapping ions in a potential well to normalize drift differences and increase sensitivity. All of these methods have drawbacks associated with their construction and ease of implementation. Therefore, it is the object of this invention to reduce or eliminate disadvantages and problems associated with prior art ion mobility instruments.
Copending U.S. application Ser. No. 09/798,030 to Fuhrer et al., filed Feb. 28, 2001 demonstrates that additional ion focusing in IMS is achieved by using a superposition of hyperbolic and periodic electric fields in a mobility cell.
Brittain, et al., in U.S. Pat. No. 5,633,497, describe the coating of the interior surfaces of an ion trap or ionization chamber with an inert, inorganic non-metallic insulator or semiconductor material for the passivation of such surfaces so as to minimize absorption, degradation or decomposition of a sample in contact with the surface.
Andrien, et al., in U.S. Pat. No. 6,600,155, describe the coating of a surface in the time-of-flight pulsing region with a dielectric film between other films, suggesting an improvement of ion beam properties before orthogonal extraction of ions into the drift region of a time-of-flight mass spectrometer.
Loboda, in U.S. Pat. No. 6,630,662 describes a method of enhancing performance of mobility separation of ions by balancing the ion drift motions accomplished by the influence of DC electric field and counter-flow of the gas. Using this balance of forces, ions are first accumulated inside the ion guide, preferably RF-ion guide, and then by changing of electric field or gas flow, gradually elute from the ion guide to some detector, preferably a TOF MS.
U.S. Pat. No. 6,707,037 to Whitehouse describes the proposed extraction of ions of both signs from a MALDI target directly located inside gas-filled RF-multi-pole ion guide with a concentration of ions along the separation axis and directing them in opposite directions under influence of axial electric field for further mass-analysis.
All of the U.S. patents, patent applications, publications referenced herein are incorporated by reference as though fully described herein.
Although much of the prior art resulted in improvements in focusing and therefore in ion throughput from the mobility cell to the mass spectrometer in tandem instruments, there is room for additional improvement in ion throughput. The inventors describe herein a mobility cell design which results in alternating regions of high and low electric field to provide improved ion focusing.